The overall goal of this project is to characterize the nature and extent of abnormalities in phospholipid (PL) metabolism that are associated with neuronal dysfunction and degeneration in Alzheimer's disease (AD). A related goal of the research is to determine whether PL abnormalities occurring in brain tissue can be detected in the cerebrospinal fluid (CSF) during life, and whether they are part of a systemic lesion and can be detected in peripheral blood (red cells and lymphocytes). There are two major hypotheses: 1. Abnormalities in the metabolism of phosphatidylcholine (PC) and possibly other PLs are associated with neuronal dysfunction and degeneration in AD and are distinct from findings in other neurodegenerative diseases or that may occur during normal aging. 2. Accuracy in the antemortem diagnosis of AD may be enhanced by detecting in body fluids the abnormalities of PL metabolism that occur in brain. In order to accomplish these goals, we will measure levels of water-soluble precursors and metabolites of PC and other PLs catalytic enzyme activities, in brain tissue obtained at autopsy from patients with AD, and Huntington's disease (HD), and from two groups of control subjects: one with ages between 20 and 40, and the second with ages between 60 and 80. Brain samples will be from frontal, parietal, temporal, and occipital cortex; dentate nucleus of cerebellum; and subcortical nuclei caudate, midline thalamus, ventral forebrain Ch 1-4 group, hippocampus, and amygdala. In clinical studies, CSF and blood samples will be obtained from patients with sporadic and familial forms of AD and from control subjects in ten 20 to 40 age range and in the 60 to 80 age range. The same water-soluble PL precursors and metabolites measured in brain will be measured in CSF and blood cells, and, in addition, PL catalytic enzyme activities will be measured in blood cells. This project is multidisciplinary and involves investigators from the fields of neurology,k neuropathology, biochemistry and statistics. The proposed research takes advantage of resources in the Massachusetts Alzheimer's Disease Research Center and also benefits from research at MGH on the genetics of AD. Identification of characteristic abnormalities in PL metabolism in brains of patients with AD may provide new explanations for neuronal dysfunction and death; detection of these abnormalities in blood or CSF samples would be a welcomed aid to the accurate antemortem diagnosis of AD.